tbuckley/cabot-search huggingface dataset:
A Novel Signal‐On Electrochemiluminescence Immunosensor for the Detection of NSCLC Antigen Biomarker Based on New Co‐Reaction Accelerators
Authors: Lei Guo, Zhaode Mu, Min Qing, Jing Zhou, Huizhen Li, Lulu Wang, Muyue Zhong, Lijuan Bai
Journal: Advanced Healthcare Materials (2022)

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with substantial morbidity and mortality. Herein, a new signal-on electrochemiluminescence (ECL) immunosensor based on multiple amplification strategies is constructed for ultrasensitive detection of cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) biomarker related to NSCLC. Polyethyleneimine (PEI) functionalized MXene is decorated with NiMn layer double hydroxide (NiMn LDH) to form MXene-PEI-NiMn LDH composite. Specially, the La-MOF@ZIF-67 bimetallic organic framework (named as LZBM) and MXene-PEI-NiMn LDH both served as coreaction accelerators to improve the ECL emission of the luminol-H2 O2 system. To be specific, Au nanoparticles (AuNPs) coated MXene-PEI-NiMn LDH is applied to immobilize primary CYFRA21-1 antibody (Ab1 ), while AuNPs decorated LZBM was used for the loading of luminol and secondary CYFRA21-1 antibody (Ab2 ) to form tracer label. Therefore, the ECL signal of the sandwich-type immunosensor is significantly enhanced due to the high loading capability for luminol and the synergistic catalytic ability for the decomposition of H2 O2 into reactive oxygen species (ROS). Under the optimal experimental conditions, the ECL immunosensor exhibited good analytical performances for CYFRA21-1 detection with a wide linear range (100 fg mL-1 -100 ng mL-1 ) and a low limit of detection (85.20 fg mL-1 ), providing a promising method for early diagnosis of NSCLC.
GLP-1 Receptor Agonists for the Reduction of Atherosclerotic Cardiovascular Risk in Patients With Type 2 Diabetes
Authors: Nikolaus Marx, Mansoor Husain, Michael Lehrke, Subodh Verma, Naveed Sattar
Journal: Circulation (2022)

Patients with type 2 diabetes are at high risk for development of cardiovascular disease, including myocardial infarction, stroke, heart failure, and cardiovascular death. Multiple large cardiovascular outcome trials with novel glucose-lowering agents, namely SGLT2i (SGLT2 inhibitors) and GLP-1 RA (GLP-1 receptor agonists), have demonstrated robust and significant reductions of major adverse cardiovascular events and additional cardiovascular outcomes, such as hospitalizations for heart failure. This evidence has changed the landscape for treatment of patients with type 2 diabetes. Both diabetes and cardiology guidelines and professional societies have responded to this paradigm shift by including strong recommendations to use SGLT2i and/or GLP-1 RA, with evidence-based benefits to reduce cardiovascular risk in high-risk individuals with type 2 diabetes, independent of the need for additional glucose control. GLP-1 RA were initially developed as glucose-lowering drugs because activation of the GLP-1 receptor by these agents leads to a reduction in blood glucose and an improvement in postprandial glucose metabolism. By stimulating GLP-1R in hypothalamic neurons, GLP-1 RA additionally induce satiety and lead to weight loss. Data from cardiovascular outcome trials demonstrated a robust and consistent reduction in atherothrombotic events, particularly in patients with established atherosclerotic cardiovascular disease. Despite the consistent evidence of atherosclerotic cardiovascular disease benefit from these trials, the number of patients receiving these drugs remains low. This overview summarizes the experimental and clinical evidence of cardiovascular risk reduction offered by GLP-1 RA, and provides practical information on how these drugs should be implemented in the treatment of type 2 diabetes in the cardiology community.
Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance
Authors: Niklas Klümper, Damian J. Ralser, Jörg Ellinger, Florian Roghmann, Julia Albrecht, Eduard Below, Abdullah Alajati, Danijel Sikic, Johannes Breyer, Christian Bolenz, Friedemann Zengerling, Philipp Erben, Kristina Schwamborn, Ralph M. Wirtz, Thomas Horn, Dora Nagy, Marieta Toma, Glen Kristiansen, Thomas Büttner, Oliver Hahn, Viktor Grünwald, Christopher Darr, Eva Erne, Steffen Rausch, Jens Bedke, Katrin Schlack, Mahmoud Abbas, Stefanie Zschäbitz, Constantin Schwab, Alexander Mustea, Patrick Adam, Andreas Manseck, Bernd Wullich, Manuel Ritter, Arndt Hartmann, Jürgen Gschwend, Wilko Weichert, Franziska Erlmeier, Michael Hölzel, Markus Eckstein
Journal: Clinical Cancer Research (2022)

The antibody-drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET). Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4-negative/weak (H-score 0-99) versus moderate/strong (H-score 100-300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9-induced polyclonal NECTIN-4 knockouts. In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0-140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001). Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV. See related commentary by Aggen et al., p. 1377.
Hippocalcin-Like 1 blunts liver lipid metabolism to suppress tumorigenesis via directly targeting RUVBL1-mTOR signaling
Authors: Tao Chen, Zhiqing Yuan, Zhou Lei, Jinlin Duan, Junyan Xue, Ting Lu, Guouan Yan, Lei Zhang, Yanfeng Liu, Qiwei Li, Yonglong Zhang
Journal: Theranostics (2022)

Rationale: Hepatocellular carcinoma (HCC) is one of the most severe cancers worldwide, with few effective targeted therapies for HCC.Lipid metabolic reprogramming is emerged as a hallmark of cancer metabolism that guides response to antitumoral therapies.Such lipid metabolic alteration in cancers is critically regulated by the mammalian target of rapamycin mTOR, which is considered as a promising therapeutic target.Despite efforts, mTOR inhibitors (mTORi) have produced limited response clinically, partly due to incomplete knowledge of mTORC1 addiction in cancers.Methods: CRISPR-Cas9 system was used to establish Hpcal1 null mice.The liver cancer model in mice was generated using Hpcal1-deficient mice with diethylnitrosamine (DEN) /CCL4 or MYC/Trp53 -/-via hydrodynamic tail-vein injection.RNA-sequencing (RNA-seq) was used to identify potential signaling pathways.The expression of HPCAL1 and mTOR signaling were determined using quantitative polymerase chain reaction (qPCR), western blot and immunohistochemistry.The role of Hpcal1 in liver tumorigenesis and its response to mTORi was assessed by CCK-8 measurements, colony formation assay and in mouse model.Results: In this study, we identified hippocalcin-like protein 1 (HPCAL1) as an important negative regulator of de novo lipid biosynthesis and mTOR signaling activation, limiting liver tumorigenesis and establishing a metabolic vulnerability of HCC in mice.Genetic loss of HPCAL1 rendered HCC mTORC1-addicted and sensitive to mTORi AZD-8055 in vitro and in vivo.Importantly, HPCAL1 expression was inversely correlated with the levels of mTOR phosphorylation and several critical lipid biosynthesis enzymes in human specimens.Mechanistically, HPCAL1 directly bound to RuvB Like AAA ATPase 1 (RUVBL1), inhibiting the assembly of TEL2-TTI1-TTI2 (TTT)-RUVBL complex and subsequent leading the mTOR signaling suppression. Conclusion:We uncover a metabolic vulnerability and mTOR addiction in HCC with HPCAL1 loss that provides a selective therapeutic window for HCC with mTORC1 hyperactivation using mTORi.
MMP 9-instructed assembly of bFGF nanofibers in ischemic myocardium to promote heart repair
Authors: Yaguang Wang, Di Wang, Chao Wu, Bin Wang, Shufang He, Hua Wang, Gaolin Liang, Ye Zhang
Journal: Theranostics (2022)

Background: The only effective treatment for myocardial infarction (MI) is the timely restoration of coronary blood flow in the infarcted area, but further reperfusion exacerbates myocardial injury and leads to distal coronary no-reflow, which affects patient prognosis. Angiogenesis could be an important therapeutic strategy for re-establishing the blood supply to save the ischemic myocardium after MI. Basic fibroblast growth factor (bFGF) has been shown to promote angiogenesis. However, direct intravenous administration of bFGF is not a viable option given its poor half-life in vivo. Methods: Herein, we developed a peptide Lys-Lys-Pro-Leu-Gly-Leu-Ala-Gly-Phe-Phe (K2) to encapsulate bFGF to form bFGF@K2 micelle and proposed an enzyme-instructed self-assembly (EISA) strategy to deliver and slowly release bFGF in the ischemic myocardium. Results: The bFGF@K2 micelle exerted a stronger cardioprotective effect than free bFGF in a rat model of myocardial ischemia-reperfusion (MI/R). In vitro results revealed that the bFGF@K2 micelle could be cleaved by matrix metallopeptidase 9 (MMP-9) to yield bFGF@Nanofiber through amphipathic changes. In vivo experiments indicated that intravenous administration of bFGF@K2 micelle could lead to their restructuring into bFGF@Nanofiber and long term retention of bFGF in the ischemic myocardium of rat due to high expression of MMP-9 and assembly-induced retention (AIR) effect, respectively. Twenty-eight days after MI/R model establishment, bFGF@K2 micelle treatment significantly reduced fibrosis and improved cardiac function of the rats. Conclusion: We predict that our strategy could be applied in clinic for MI treatment in the future.
Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates
Authors: Evan C. Chen, Helen Gandler, Isidora Tošić, Geoffrey G. Fell, Ashlee Fiore, Olga Pozdnyakova, Daniel J. DeAngelo, Ilene Galinsky, Marlise R. Luskin, Martha Wadleigh, Eric S. Winer, Rebecca Leonard, Kelsey O'Day, Adrienne de Jonge, Donna Neuberg, A. Thomas Look, Richard M. Stone, David A. Frank, Jacqueline S. Garcia
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and require new therapies. In AML, autocrine production of hepatocyte growth factor (HGF) drives MET signaling that promotes myeloblast growth and survival, making MET an attractive therapeutic target. MET inhibition exhibits activity in AML preclinical studies, but HGF upregulation by the FGFR pathway is a common mechanism of resistance. Patients and Methods: We performed preclinical studies followed by a Phase I trial to investigate the safety and biological activity of the MET inhibitor merestinib in combination with the FGFR inhibitor LY2874455 for patients with R/R AML. Study Cohort 1 underwent a safety lead-in to determine a tolerable dose of single-agent merestinib. In Cohort 2, dose-escalation of merestinib and LY2874455 was performed following a 3+3 design. Correlative studies were conducted. Results: The primary dose-limiting toxicity (DLT) observed for merestinib alone or with LY2874455 was reversible grade 3 transaminase elevation, occurring in 2 of 16 patients. Eight patients had stable disease and one achieved complete remission (CR) without measurable residual disease. Although the MTD of combination therapy could not be determined due to drug supply discontinuation, single-agent merestinib administered at 80 mg daily was safe and biologically active. Correlative studies showed therapeutic plasma levels of merestinib, on-target attenuation of MET signaling in leukemic blood, and increased HGF expression in bone marrow aspirate samples of refractory disease. Conclusions: We provide prospective, preliminary evidence that MET and FGFR are biologically active and safely targetable pathways in AML.
circHIPK3 prevents cardiac senescence by acting as a scaffold to recruit ubiquitin ligase to degrade HuR
Authors: Fengzhi Ding, Lin Lu, Chengjie Wu, Xiangbin Pan, Bin Liu, Yu Zhang, Yanli Wang, Weiliang Wu, Bing Yan, Yuqing Zhang, Xi-Yong Yu, Yangxin Li
Journal: Theranostics (2022)

Rational: Senescence is a major aging process that contributes to the development of cardiovascular diseases, but the underlying molecular mechanisms remain largely unknown.One reason is due to the lack of suitable animal models.We aimed to generate a cardiomyocyte (CM)-specific senescent animal model, uncover the underlying mechanisms, and develop new therapies for aging associated cardiac dysfunction. Methods:The gain/loss of circHIPK3 approach was used to explore the role of circHIPK3 in cardiomyocyte (CM) senescence.To investigate the mechanisms of circHIPK3 function in cardiac senescence, we generated CM-specific tamoxifen-induced circHIPK3 knockout (CKO) mice.We also applied various analyses including PCR, Western blot, nuclear and cytoplasmic protein extraction, immunofluorescence, echocardiography, RNA immunoprecipitation assay, RNA-pulldown assay, and co-immunoprecipitation.Results: Our novel CKO mice exhibited worse cardiac function, decreased circHIPK3 expression and telomere length shortening in the heart.The level of the senescence-inducer p21 in the hearts of CKO mice was significantly increased and survival was poor compared with control mice.In vitro, the level of p21 in CMs was significantly decreased by circHIPK3 overexpression, but increased by circHIPK3 silencing.We showed that circHIPK3 was a scaffold for p21 mRNA-binding protein HuR and E3 ubiquitin ligase β-TrCP.circHIPK3 silencing weakened the interaction between HuR and β-TrCP, reduced HuR ubiquitination, and enhanced the interaction between HuR and p21 mRNA.Moreover, we found that mice injected with human umbilical cord mesenchymal stem cell-derived exosomes (UMSC-Exos) showed increased circHIPK3 levels, decreased levels of p21, longer telomere length, and good cardiac function.However, these beneficial effects exerted by UMSC-Exos were inhibited by silencing circHIPK3.Conclusions: We successfully generated CM-specific CKO mice for aging research.Our results showed that deletion of circHIPK3 led to exaggerated CM senescence and decreased cardiac function.As a scaffold, circHIPK3 enhanced the binding of E3 ubiquitin ligase β-TrCP and HuR in the cytoplasm, leading to the ubiquitination and degradation of HuR and reduced p21 activity.In addition, UMSC-Exos exerted an anti-senescence and cardio-protective effect by delivering circHIPK3.These findings pave the way to the development of new therapies for aging associated cardiac dysfunction.
Automated assembly scaffolding using RagTag elevates a new tomato system for high-throughput genome editing
Authors: Michael Alonge, Ludivine Lebeigle, Melanie Kirsche, Katie Jenike, Shujun Ou, Sergey Aganezov, Xingang Wang, Zachary B. Lippman, Michael C. Schatz, Sebastian Soyk
Journal: Genome biology (2022)

Advancing crop genomics requires efficient genetic systems enabled by high-quality personalized genome assemblies. Here, we introduce RagTag, a toolset for automating assembly scaffolding and patching, and we establish chromosome-scale reference genomes for the widely used tomato genotype M82 along with Sweet-100, a new rapid-cycling genotype that we developed to accelerate functional genomics and genome editing in tomato. This work outlines strategies to rapidly expand genetic systems and genomic resources in other plant species.
Promotion of Knee Cartilage Degradation by <scp>IκB</scp> Kinase ε in the Pathogenesis of Osteoarthritis in Human and Murine Models
Authors: Taisuke Uchida, Yukio Akasaki, Takuya Sueishi, Ichiro Kurakazu, Masakazu Toya, Masanari Kuwahara, Ryota Hirose, Yuki Hyodo, Hidetoshi Tsushima, Martin K. Lotz, Yasuharu Nakashima
Journal: Arthritis & Rheumatology (2022)

NF-κB signaling is an important modulator in osteoarthritis (OA), and IκB kinase ε (IKKε) regulates the NF-κB pathway. This study was undertaken to identify the functional involvement of IKKε in the pathogenesis of OA and the effectiveness of IKKε inhibition as a modulatory treatment.IKKε expression in normal and OA human knee joints was analyzed immunohistochemically. Gain- or loss-of-function experiments were performed using human chondrocytes. Furthermore, OA was surgically induced in mice, followed by intraarticular injection of BAY-985, an IKKε/TANK-binding kinase 1 inhibitor, into the left knee joint every 5 days for 8 weeks. Mice were subsequently examined for histologic features of cartilage damage and inflammation.IKKε protein expression was increased in human OA cartilage. In vitro, expression levels of OA-related factors were down-regulated following knockdown of IKKε with the use of small interfering RNA in human OA chondrocytes or following treatment with BAY-985. Conversely, IKKε overexpression significantly increased the expression of OA-related catabolic mediators. In Western blot analysis of human chondrocytes, IKKε overexpression increased the phosphorylation of IκBα and p65. In vivo, intraarticular injection of BAY-985 into the knee joints of mice attenuated OA-related cartilage degradation and hyperalgesia via NF-κB signaling.These results suggest that IKKε regulates cartilage degradation through a catabolic response mediated by NF-κB signaling, and this could represent a potential target for OA treatment. Furthermore, BAY-985 may serve as a major disease-modifying compound among the drugs developed for OA.
Racial and ethnic disparities in mortality among breast cancer survivors after a second malignancy
Authors: Zhengyi Deng, Miranda R Jones, Mei-Cheng Wang, Antonio C Wolff, Kala Visvanathan
Journal: JNCI Journal of the National Cancer Institute (2022)

Racial and ethnic differences in survival after a first cancer are well established but have not been examined after a second primary cancer (SPC) despite the increasing incidence among survivors.We examined 39 029 female breast cancer survivors who developed an SPC between 2000 and 2014 in the Surveillance, Epidemiology, and End Results 18 database. Multivariable Cox proportional hazards regression for competing risks data was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for cancer and cardiovascular disease mortality after SPCs comparing Hispanic, Non-Hispanic Asian, and Non-Hispanic Black survivors with Non-Hispanic White survivors. Models were adjusted for sociodemographics, tumor characteristics, and treatments of the first and second cancer. Analyses were stratified by SPC type.During 17 years of follow-up, there were 15 117 deaths after SPCs. The risk of cancer death was 12% higher among Non-Hispanic Black survivors (HR = 1.12, 95% CI = 1.05 to 1.19) and 8% higher among Hispanic survivors (HR = 1.08, 95% CI = 1.00 to 1.16) compared with Non-Hispanic White survivors. In subgroup analyses, the strongest associations were observed among Non-Hispanic Black survivors with a second breast or uterine cancer and among Hispanic survivors with a second breast cancer. Non-Hispanic Black survivors also experienced a 44% higher risk of cardiovascular disease death after SPC diagnosis than Non-Hispanic White survivors (HR = 1.44, 95% CI = 1.20 to 1.74).Higher cancer mortality among Non-Hispanic Black and Hispanic survivors and higher cardiovascular mortality among Non-Hispanic Black survivors exist among women who survive a first breast cancer to develop an SPC. Studies focused on identifying the contributors to these disparities are needed to enable implementation of effective mitigation strategies.
Knee Alignment Correction by High Tibial Osteotomy Reduces Symptoms and Synovial Inflammation in Knee Osteoarthritis Accompanied by Macrophage Phenotypic Change From <scp>M1</scp> to <scp>M2</scp>
Authors: Shigeo Yoshida, Kohei Nishitani, Hiroyuki Yoshitomi, Shinichi Kuriyama, Shinichiro Nakamura, Takayuki Fujii, Motoo Saito, Yu Kobori, Akinori Murakami, Koichi Murata, Hiromu Ito, Hideki Ueno, Shuichi Matsuda
Journal: Arthritis & Rheumatology (2022)

This study aimed to determine whether alignment correction by high tibial osteotomy (HTO) can change the biologic intraarticular microenvironment of osteoarthritic (OA) knees.Synovial tissue (ST) and fluid (SF) were collected from the affected knees of 31 OA patients during initial HTO and plate removal surgeries. Changes in gene expression in ST were investigated by microarray and real-time polymerase chain reaction (PCR). ST specimens were also evaluated histologically using synovitis scores and immunofluorescence staining to determine macrophage polarity. Cytokines and chemokines in SF were analyzed by enzyme-linked immunosorbent assays. The mechanism of macrophage polarization was investigated in human peripheral blood mononuclear cell-derived macrophages and fibroblast-like synoviocytes (FLS) stimulated with cartilage fragments. We also evaluated Spearman correlations between Knee Injury and Osteoarthritis Outcome scores (KOOS) and macrophage-related gene expression.The microarray results indicated down-regulated inflammatory genes and pathways. Real-time PCR determined that genes expressing proinflammatory IL1B and IL6 were down-regulated and M2 macrophage-related IL1RA, IL10, CCL18, and CD206 were up-regulated. Histologic findings revealed attenuated synovitis scores and a shift from M1 to M2 macrophages. Interleukin-1β (IL-1β) concentrations in SF decreased after HTO. Cartilage fragments were responsible for M1 macrophage polarization and proinflammatory gene and protein expression in macrophages, whereas cartilage fragments up-regulated only IL-6 protein in FLS. Postoperative KOOS positively correlated with the expression of the M2-related genes CCL18 and CD206.Correction of lower limb alignment with HTO attenuated synovial inflammation and changed macrophage polarization from M1 to M2, suggesting an improved intraarticular environment in knee OA.
Is There a Role for Thromboprophylaxis in Selected Outpatients With COVID-19?—Reply
Authors: Junqing Xie, Daniel Prieto-Alhambra
Journal: JAMA Internal Medicine (2022)

JunQing Xie, BSMed, MSc; Albert Prats-Uribe, DPhil; Qi Feng, PhD; YunHe Wang, MSc; Dipender Gill, MD, PhD; Roger Paredes, MD, PhD; Dani Prieto-Alhambra, MD, PhD